Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

The [3 + 2] cycloadditions of stabilized azomethine ylides (AMYs) derived from amino esters are well-established. However, the reactions of semi-stabilized AMYs generated from decarboxylative condensation of α-amino acids with arylaldehydes are much less explored. The [3 + 2] adducts of α-amino acids could be used for a second [3 + 2] cycloaddition as well as for other post-condensation modifications. This article highlights our recent work on the development of α-amino acid-based [3 + 2] cycloaddition reactions of N–H-type AMYs in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse heterocycles related to some bioactive compounds and natural products.

There are over 300 papers on the amino acid-based decarboxylative [3 + 2] cycloadditions of N-R-type AMYs B1 (such as that derived from proline) and B2 .However, to the best of our knowledge, there are only few examples on the reactions of N-H-type semi-stabilized AMYs B3 or B4 which were either derived from special carbonyl compounds (such as isatin) [52][53][54][55] or the AMYs were reacted with uncommon alkenes as the 1,3-dipolarophiles (such as C 60 /C 70 fullerenes) [56][57][58].
Other than amino esters and amino acids shown in Scheme 1, cyclic amines can also react with arylaldehydes to form B1-type semi-stabilized AMYs.In this context, the Seidel group re-  ported the reactions of pyrrolidines 5 with arylaldehydes for the formation of AMYs B1 which then were reacted with nucleophiles to form C-H-functionalized pyrrolidines or subjected to the 1,3-dipolar cycloaddition with olefins to afford bicyclic compounds (Scheme 2A and B) [59,60].We employed cyclic amines for the synthesis of spirooxindole-pyrrolidines 7a or 7b in good stereoselectivity (Scheme 3) [61,62].
From the results shown in Scheme 2 and Scheme 3, we envisioned that pyrrolidines 3c or 3d generated from the cycloaddition of AMYs B3 or B4 could undergo a second cycloaddition to form double cycloaddition products 4a or 4b (Scheme 4).The double cycloaddition process involves two kinds of AMYs, with the first ones (N-H-type B3 or B4) derived from amino acids, while the second ones (N-R-type B1) derived from pyrrolidines 3c or 3d.It is worth noting that the double cycloaddition reaction is a pseudo-five-component reaction of amino acids with two equivalents each of aldehydes and alkenes.The first cycloaddition products 3c or 3d can also be used as intermediates for other transformations to synthesize novel heterocyclic rings via multicomponent, one-pot, and stepwise synthesis [63,64].
Presented in the following sections is our work on the development of amino acid-based decarboxylative [3 + 2] cycloadditions of N-H-type AMYs B3 and B4 for double cycloadditions.The stereochemistry of the cycloadditions and the combination of the cycloaddition with other transformations to be one-pot or stepwise reactions are also presented.

Perspective One-step synthesis of trifluoromethylated pyrrolidines
As mentioned above, the unexpected double cycloaddition and low stereoselectivity are the major challenges for [3 + 2] cyclo- addition reactions of semi-and non-stabilized AMYs derived from the condensation of amino acids with aldehydes.However, the reactions of amino acids with ketones can result in a different kind of AMYs to address the issue.The reaction of tri-fluoromethyl ketones with glycine or α-substituted amino acids generated stabilized AMY 8 which underwent cycloaddition with maleimides to give 2-CF 3 -substituted pyrrolidines 9 in 50-76% yield (Scheme 5) [65].Both the Ar and CF 3 groups can localize the negative charge and also provide steric effects to afford stereoselective cycloaddition products with 3:1 to 6:1 dr.The steric hindrance also prevents products 9 from undergoing a second cycloaddition.The control reactions of methyl ketone or benzaldehydes gave much lower yields and stereoselectivity because of the lacking CF 3 group.This was the first example of synthesizing 2-CF 3 -substituted pyrrolidines via decarboxylative [3 + 2] cycloaddition which is more efficient than multistep and metal-assisted syntheses reported in the literature [66,67].
After the method development work, a pseudo-five-component double cycloaddition reaction of glycine with two equivalents each of arylaldehydes and N-substituted maleimides was carried out in EtOH as a protic solvent at 90 °C for 3 h to afford pyrrolizidines 10 in 73-93% yield with greater than 9:1 dr (Scheme 6).The scope of the reaction could be readily extended for α-substituted amino acids, such as alanine, leucine, serine, and norvaline to give products 11a-f in 53-88% yields with greater than 8.5 dr (Scheme 7).The reactions with leucine and phenylglycine (R 2 = iPr and Ph) as amino acids gave mainly mono-cycloaddition products and very little double cycloaddition products 11g and 11h due to the steric hindrance of the R 2 group.
The stereochemistry of products 10 and 11 was confirmed by X-ray crystal structure and the 1 H NMR analysis of both the major and minor diastereomers [69].The first cycloaddition gives adducts 12 and 12' as a diastereomeric mixture.At the second cycloaddition, both major and minor adducts from the first cycloaddition generate the same products 10 or 11 (Scheme 8).
We also evaluated the double cycloadditions in two operational steps by using two different sets of aldehydes and maleimides to afford products 13a-d in 45-60% yields with 2:1 to 3:1 dr (Scheme 9).The low diastereoselectivity is caused by the different R 2 /R 2' and R 3 /R 3' groups which no longer have the same stereochemistry as that shown in Scheme 8.

Double cycloadditions for bis[spirooxindolepyrrolizidine] compounds
After completing the pseudo-five-component double cycloaddition reactions leading to polycyclic pyrrolizidines shown in Scheme 6 and Scheme 7, we then conducted similar reactions in order to synthesize spirooxindole-pyrrolidines.This unique ring skeleton exists in some natural products and biologically active compounds such as (−)-horsfiline, (+)-alstonisine, pteropodine and spirotryprostatin A (Figure 3) [70].
We expected that using olefinic oxindoles 14 as alkenes for the [3 + 2] cycloaddition could afford spirooxindole-pyrrolizidines.The method development revealed that recyclable zeolite HY acid is a good catalyst for the cycloaddition [70].Thus, the zeolite HY-catalyzed reaction of glycine with two equiv each of arylaldehydes and olefinic oxindoles 14 in EtOH at 90 °C for 6 h gave bis[spirooxindole-pyrrolizidine] compounds 15a-g in 60-73% yields with up to 6:1 dr (Scheme 10).It is worth noting that this pseudo-five-component reaction gives butterfly-shaped molecules which have a plane of symmetry.The stereochemistry of the products was confirmed by X-ray crystal structure and NMR analysis.The reaction mechanism shown in Scheme 11 suggests that a semi-stabilized AMY 16 generated from the reaction of glycine and arylaldehydes undergoes a [3 + 2] cycloaddition with 14a via the favorable endo-transition state A to give spirooxindole-pyrrolizidine 17 which spontaneously reacts with another equiv of arylaldehyde to form ylide 18 in the presence of zeolite HY.The second [3 + 2] cycloaddition of 18 with 14a affords product 15a as a major product through an endocycloaddition and 15a' as a minor diastereomeric product through an exo-cycloaddition.Scheme 6: Double cycloadditions with glycine for the synthesis of products 10 (dr > 9:1).

One-pot synthesis of triazolobenzodiazepines
Other than the multicomponent double cycloaddition reactions shown in the last section, we also utilized the first cycloaddition products for post-condensation reactions to generate new heterocyclic scaffolds.α-Substituted amino acids, such as 2-aminoisobutyric acid, could be used to block the second cycloaddition.Shown in Scheme 12 is a method development for the stepwise synthesis of triazolobenzodiazepines.The reaction of 2-azidobenzaldehyde, 2-aminoisobutyric acid and N-ethylmaleimide in MeCN under the catalysis of AcOH at 110 °C for 6 h afforded the monocycloaddition product 19a in 93% LC yield [71].The isolated compound 19a was used for an N-propargylation to produce compound 20a in 94% LC yield.
Our next goal was to convert the stepwise reaction process into a one-pot synthesis.After optimizing the reaction conditions, a one-pot two-step reaction was developed by the reaction of 2-azidobenzaldehydes, 2-substituted amino acids and maleimides with AcOH as a catalyst in MeCN at 110 °C for 6 h to afford the monocycloaddition compounds.Without isolation, the reaction mixtures were then used for the N-propargylation in the presence of K 2 CO 3 under microwave heating at 110 °C for 1 h to give triazolobenzodiazepines 21a-f in 35-65% yields with 2:1 to 7:1 dr (Scheme 13).Other than 2-aminoisobutyric acid, phenylglycine and valine with Ph or iPr groups could also  be used for the synthesis of the monocycloaddition products for the post-condensation reactions.It is worth noting that in the one-pot synthesis involving an intramolecular click reaction, no Cu catalyst was used.A similar reaction sequence using stabilized AMYs was also reported from our lab [72].The triazolobenzodiazepines obtained through this highly efficient one-pot synthesis have structure similarity with some drug molecules shown in Figure 4 [71].

Stepwise synthesis of pyrrolo[2,1-a]isoquinolines
A stepwise synthesis involving [3 + 2] cycloaddition, N-allylation and Heck reactions has been developed for the synthesis of pyrrolo[2,1-a]isoquinolines.The reaction of 2-bromobenzalde-hydes, 2-aminoisobutyric acid, and maleimides in MeCN under the catalysis of AcOH at 110 °C for 6 h afforded the cycloaddition products 26.The purified intermediates were used for the one-pot N-allylation with allyl bromide to afford intermediate 25 followed by a Pd-catalyzed Heck reaction to give products 26 in 65-78% yields (Scheme 16) [75].The pyrrolo[2,1a]isoquinoline core installed by this route can be found in some natural products and synthetic compounds with antitumor, antibacterial, antiviral, antioxidizing, and other biological activities (Figure 6) [75].

One-pot double annulations for the synthesis of tetrahydropyrrolothiazoles
The unique tetrahydropyrrolothiazole and spiro[indole-tetrahydropyrrolothiazole] scaffolds are found in bioactive compounds such as those shown in Figure 7 [76,77].Using cysteine as a key reactant, we developed a pseudo-four-component reaction    for the synthesis of tetrahydropyrrolothiazole derivatives.The reaction of cysteine with two equiv of arylaldehydes and one equiv of maleimides in EtOH at 90 °C for 12 h afforded tetrahy-dropyrrolothiazoles 29 in 66-79% yields with up to 7:1 dr (Scheme 17) [76].Using olefinic oxindoles to replace maleimides, the reactions gave spiro[indoline-tetrahydropyrrolothia-  zole] products 30 in 55-70% with greater than 4:1 dr [76].The reaction mechanism suggests that the reaction of cysteine with arylaldehydes gives N,S-acetals 27 which convert to AMYs 28 after decarboxlyation.Cycloaddition of 28 with maleimides or olefinic oxindoles gives products 29 and 30, respectively.The reactions could be carried out as a two-step synthesis using two different arylaldehydes to give products 31 in 43-72% yields with greater than 4:1 dr (Scheme 18).A similar reaction sequence based on a [3 + 2] cycloaddition of stabilized AMYs has been reported by our lab [78].

Conclusion
The amino acid-based decarboxylative [3 + 2] cycloaddition reactions developed from our lab are summarized in this paper.The semi-stabilized N-H-type azomethine ylides derived from amino acids could be used for multicomponent, one-pot, and multistep reactions in the synthesis of heterocyclic compounds.The methods have advantages of using readily available starting materials, performing streamlined reactions, producing diverse product structures, and having high pot, atom, and step economy (PASE) [79][80][81] for the diversity-oriented synthesis (DOS) [82][83][84][85][86][87][88].The work presented in this paper may also be helpful to understand the reaction mechanism and stereoselectivity of semi-stabilized N-H-type AMYs.We hope the new development for 1,3-dipolar cycloaddition chemistry can be used for the synthesis of bioactive heterocyclic compounds in medicinal and drug discovery programs.

Scheme 8 :
Scheme 8: Stereochemistry for the formation of products 10 or 11.